Empa Add on to Insulin in Japanese Patient With Type 1 Diabetes Mellitus

A Phase II, Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Once Daily, Oral Doses of Empagliflozin as Adjunctive to Insulin Therapy for 28 Days in Japanese Patients With Type 1 Diabetes Mellitus

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of once daily oral doses of empagliflozin in Japanese patients with type 1 diabetes mellitus as adjunctive therapy to insulin.

Inclusion criteria:

• Signed and dated written informed consent by the date of Visit 1 (screening) in accordance with Good Clinical Practice (GCP) and local legislation
• Japanese male or female patient receiving insulin for treatment of documented diagnosis of type 1 diabetes mellitus (T1DM) for at least 1 year at the time of Visit 1 (screening).
• Fasting C-peptide value of < 0.6 ng/mL at Visit 2 (placebo run-in) measured by the central laboratory
• Use of, and be willing, based on the investigator's judgment, to continue throughout the duration of the trial Multiple daily injection(MDI) of insulin consisting of at least 1 basal insulin injection and at least 3 daily bolus injections The total daily insulin dose must be>=0.3 U/kg and <=1.5 U/kg at Visit 1 (screening)
• HbA1c of 7.5% to 10.0% at Visit 1 (screening) measured by the central laboratory and provided that the patients HbA1c does not increase by > 0.5% within 3 months before Visit 1 (screening)
• Based on the investigator's judgment, patient must have a good understanding of his/her disease and how to manage it, and be willing and capable of performing the following study assessments (assessed at Visits 1 to 3 and just before randomization)
• patient-led management and adjustment of insulin therapy
• reliable approach to insulin dose adjustment for meals, such as carbohydrate counting
• reliable and regular home-based blood glucose monitoring
• recognize the symptoms of DKA (Diabetic Ketoacidosis), and reliably monitor for ketones
• implementation of an established "sick day" management regimen
• Age >=20 years and <=65 years at Visit 1 (screening)
• Body mass index (BMI) >=18.5 kg/m2 and<=35.0 kg/m2 at Visit 1 (screening)
• Estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73m² and <=150 mL/min/1.73m² as calculated by Japanese equation based on creatinine measured by the central laboratory at Visit 1 (screening)
• Compliance with trial drug administration must be between 80% and 120% during the placebo run-in period, to be judged at Visit 4 and before randomization

Exclusion criteria:

• History of T2DM (Type 2 Diabetes Mellitus), maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis
• Pancreas, pancreatic islet cells or renal transplant recipient
• T1DM treatment with any other anti-hyperglycaemic drug (e.g., metformin, alpha-glycosidase inhibitors, glucagon-like-peptide 1 (GLP-1) receptor agonists, SGLT-2 (Sodium-Glucose co-transporter-2) inhibitors, pramlintide, inhaled insulin, pre-mixed insulins, etc.) within 3 months except subcutaneous basal and bolus insulin before Visit 1 (screening) or any history of clinically relevant hypersensitivity according to the investigator's judgment
• Occurrence of severe hypoglycemia involving coma and/or seizure that required hospitalization or hypoglycemia-related treatment by an emergency physician or paramedic within 3 months before Visit 1 (screening)
• Occurrence of DKA within 3 months before Visit 1 (screening) and until randomization at Visit 4 (Day 1)
• Irregular sleep/wake cycle (e.g., patients who habitually sleep during the day and work during the night) based on the investigator's judgment
• Acute coronary syndrome (non-STEMI, STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 3 months before Visit 1 (screening)
• Diagnosis of severe gastro paresis based on investigator's judgment
• Diagnosis of brittle diabetes based on the investigator's judgment
• Indication of liver impairment, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 (screening) as measured by the central laboratory
• Eating disorders such as bulimia or anorexia nervosa
• Treatment with anti-obesity drugs (e.g., Mazindol), surgery or aggressive diet regimen leading to unstable body weight (based on the investigator's judgment) 3 months before Visit 1 (screening) and until randomization
• Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1 (screening). Inhaled use of corticosteroids (e.g., for asthma/chronic obstructive pulmonary disease) is acceptable
• Change in dose of thyroid hormones within 6 weeks before Visit 1 (screening) or planned change or initiation of such a therapy at Visit 1 (screening)
• Medical history of cancer or treatment for cancer in the last 5 years before Visit 1 (screening). Resected basal cell carcinoma considered cured is exempted
• Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (e.g., malaria, babesiosis, hemolytic anemia) at Visit 1 (screening)
• Pre-menopausal women (last menstruation <=1 year before informed consent) who:
• are nursing or pregnant or
• are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, intra uterine devices/systems, oral contraceptives, complete sexual abstinence, double barrier method and vasectomized partner
• Alcohol or drug abuse within 3 months before Visit 1 (screening) that would interfere with trial participation based on the investigator's judgment
• Intake of an investigational drug in another trial within 30 days before Visit 1 (screening)
• Patient not able to understand and comply with study requirements based on the investigator's judgment
• Any other clinical condition that, based on investigator's judgment, would jeopardise patient safety or would affect the study outcome (e.g. immunocompromised patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections, etc.) during trial participation